Approximately 1 million people in the United States are at risk of developing iron overload, attributable primarily to the genetic disorder known as hereditary hemochromatosis (HH). HH is now recognized as one of the most common autosomal recessive disorders, occurring in approximately 5 persons per 1,000 in populations of northern European descent, with one in 8 to 10 persons a carrier. This inborn error of iron metabolism is characterized by excessive absorption of dietary iron and progressive accumulation of iron in the body in some patients, typically reaching toxic levels by midlife. Characteristic morbidity associated with the condition includes cirrhosis of the liver, arthritis, impotence, and cardiomyopathy. Most patients with HH are homozygous for a mutation in the hemochromatosis (HFE) gene, p.C282Y (rs1800562). Prior studies established that HFE mutations act by decreasing hepcidin production. While p.C282Y homozygotes with mutations in the hepcidin gene have relatively more severe iron overload than other patients homozygous for p.C282Y alone, detailed examination of the prognostic power of serum hepcidin measurements is needed. The recently discovered hormone erythroferrone (Erfe) is also a strong candidate for a modulator of HH severity. Variations in Erfe concentrations could occur as a result of mutations or polymorphisms in the Erfe gene or its regulators, or as a result of relatively common and often subclinical hemolytic disorders. We have obtained serum samples from over 18,000 participants in the NIH Hemochromatosis and Iron Overload Screening (HEIRS) Study that members of our team enrolled at UC Irvine. Through the NIH BioLINCC biorepository, we have access to serum samples and de-identified phenotypic and genotypic data from additional subjects who were enrolled at other HEIRS sites. Because this project requires a team science approach, we will establish two complementary centers at two UC Universities. The collaboration will develop a fruitful model for improved understanding of complex genotpe-phenotype interactions, a key objective in the era of personalized medicine. This two-year R21 grant will enable us to launch cutting-edge multidisciplinary research.